AIRE is upregulated in OSCC and promotes the expression of cancer-related genes, at least in part by functional interaction with ETS1. Supporting information S1 TableSequences of the PCR primers used in this study. GUID:?F46BD5E1-9548-4EF0-8DA6-EA6E3FDAFB0E Attachment: Submitted filename: transfection, and coexpression of AIRE further increased the expression of these proteins. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition. Introduction The burden of oral cancer has significantly increased in many parts of the world, causing more than 145.000 death in 2012 worldwide [1]. Despite the advances in modern medicine, oral cancer can have devastating effects on critical life functions. About 90 percent of MCC950 sodium oral cancers are squamous cell carcinomas (OSCCs) that arise from keratinocytes of the oral mucosa. Cancer development requires the acquisition Itgb1 of several properties, such as unlimited proliferation, vascularization, and invasion [2]. Aberrant growth control in cancer cells is the consequence of accumulated disorders in multiple cell-regulatory systems. Molecular analysis of OSCCs has uncovered genetic and epigenetic alterations in several distinct driver pathways, including mitogenic signaling and cell-cycle regulatory pathways, which lead to continual and unregulated proliferation of cancer cells. In addition, cancer cells recruit surrounding non-transformed cells, such as stromal cells and inflammatory cells, to create a tumor microenvironment that fosters tumor growth and invasion. Under the influence of interaction with the tumor microenvironment, cancer cells express a unique group of proteins that are absent or expressed at very low levels in normal cells. Differentially expressed proteins in OSCC compared to normal keratinocytes include various cytokines, chemokines (for example, CXCLs), extracellular matrix proteins, matrix remodeling enzymes (for example, matrix metalloproteases (MMPs)), cell adhesion molecules, and cytoskeletal proteins [3,4]. Among these factors that characterize cancer cells, we have been interested in keratin 17 (KRT17) because it is consistently and strongly induced in OSCC, and because of its unique functions. Keratins are a family of intermediate filaments that are indispensable for the structural stability of epithelial cells. KRT17 is regarded a stress-response keratin that is not expressed or at a very low level in normal squamous epithelium and is induced under pathological conditions, such as MCC950 sodium wound healing, inflammation, and cancer [5]. Interestingly, KRT17 has been recently reported to interact with AIRE [6]. was first identified as a causative gene for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, which gives rise to multiple endocrine disorders, chronic mucocutaneous candidiasis, and various ectodermal defects. AIRE consists of four domains, including a caspase recruitment domain/homogeneously staining region (CARD/HSR) domain that drives nuclear localization and oligomerization, an Sp100, AIRE, NucP41/75, DEAF1 (SAND) domain, and plant homeodomain 1 (PHD1) and PHD2 domains. The closest homolog of AIRE is Sp100, which shares the CARD, MCC950 sodium SAND, and PHD domains [7]. AIRE localizes in the nucleus in discrete, punctate structures that resemble promyelocytic leukemia nuclear bodies, which contain Sp100 family members. The nuclear localization and the presence of domains that are shared by transcription factors suggested a role for AIRE in the regulation of gene expression, and indeed, numerous studies have demonstrated that AIRE functions as a transcriptional activator [7]. AIRE is expressed in medullary thymic epithelial cells (mTECs), in which it induces ectopic expression of peripheral tissue-specific antigens, thereby facilitating the elimination of self-reactive T cells. AIRE expression has been also reported in extrathymic tissues, including epidermal keratinocytes [8C11]. In the mouse epidermis, Aire is induced by inflammatory or tumorigenic stimuli, and.